Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing domina...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/66277 |
| _version_ | 1811235776895123456 |
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| author | Barbara H Stokes Satish K Dhingra Kelly Rubiano Sachel Mok Judith Straimer Nina F Gnädig Ioanna Deni Kyra A Schindler Jade R Bath Kurt E Ward Josefine Striepen Tomas Yeo Leila S Ross Eric Legrand Frédéric Ariey Clark H Cunningham Issa M Souleymane Adama Gansané Romaric Nzoumbou-Boko Claudette Ndayikunda Abdunoor M Kabanywanyi Aline Uwimana Samuel J Smith Olimatou Kolley Mathieu Ndounga Marian Warsame Rithea Leang François Nosten Timothy JC Anderson Philip J Rosenthal Didier Ménard David A Fidock |
| author_facet | Barbara H Stokes Satish K Dhingra Kelly Rubiano Sachel Mok Judith Straimer Nina F Gnädig Ioanna Deni Kyra A Schindler Jade R Bath Kurt E Ward Josefine Striepen Tomas Yeo Leila S Ross Eric Legrand Frédéric Ariey Clark H Cunningham Issa M Souleymane Adama Gansané Romaric Nzoumbou-Boko Claudette Ndayikunda Abdunoor M Kabanywanyi Aline Uwimana Samuel J Smith Olimatou Kolley Mathieu Ndounga Marian Warsame Rithea Leang François Nosten Timothy JC Anderson Philip J Rosenthal Didier Ménard David A Fidock |
| author_sort | Barbara H Stokes |
| collection | DOAJ |
| description | The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing of point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance. |
| first_indexed | 2024-04-12T11:57:50Z |
| format | Article |
| id | doaj.art-3358baaa1cad40f3a6991b0106481a5a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T11:57:50Z |
| publishDate | 2021-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3358baaa1cad40f3a6991b0106481a5a2022-12-22T03:33:57ZengeLife Sciences Publications LtdeLife2050-084X2021-07-011010.7554/eLife.66277Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitnessBarbara H Stokes0https://orcid.org/0000-0001-9519-487XSatish K Dhingra1Kelly Rubiano2https://orcid.org/0000-0002-4149-4030Sachel Mok3https://orcid.org/0000-0002-9605-0154Judith Straimer4Nina F Gnädig5Ioanna Deni6https://orcid.org/0000-0002-5266-8243Kyra A Schindler7Jade R Bath8Kurt E Ward9https://orcid.org/0000-0002-3614-436XJosefine Striepen10Tomas Yeo11https://orcid.org/0000-0003-2923-6060Leila S Ross12Eric Legrand13Frédéric Ariey14Clark H Cunningham15Issa M Souleymane16Adama Gansané17Romaric Nzoumbou-Boko18Claudette Ndayikunda19Abdunoor M Kabanywanyi20https://orcid.org/0000-0002-2980-0429Aline Uwimana21Samuel J Smith22Olimatou Kolley23Mathieu Ndounga24Marian Warsame25Rithea Leang26François Nosten27https://orcid.org/0000-0002-7951-0745Timothy JC Anderson28Philip J Rosenthal29Didier Ménard30David A Fidock31https://orcid.org/0000-0001-6753-8938Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States; Department of Microbiology and Immunology, University of Otago, Dunedin, New ZealandDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United StatesMalaria Genetics and Resistance Unit, Institut Pasteur, INSERM U1201, CNRS ERL9195, Paris, FranceInstitut Cochin, INSERM U1016, Université Paris Descartes, Paris, FranceDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United StatesProgramme National de Lutte Contre le Paludisme au Tchad, Ndjamena, ChadCentre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina FasoLaboratoire de Parasitologie, Institut Pasteur de Bangui, Bangui, Central African RepublicUniversity Teaching Hospital of Kamenge, Bujumbura, BurundiIfakara Health Institute, Dar es Salaam, United Republic of TanzaniaMalaria and Other Parasitic Diseases Division, Rwanda Biomedical Centre, Kigali, RwandaNational Malaria Control Program, Freetown, Sierra LeoneNational Malaria Control Program, Banjul, GambiaProgramme National de Lutte Contre le Paludisme, Brazzaville, Democratic Republic of the CongoSchool of Public Health and Community Medicine, University of Gothenburg, Gothenburg, SwedenNational Center for Parasitology, Entomology & Malaria Control, Phnom Penh, CambodiaShoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United KingdomTexas Biomedical Research Institute, San Antonio, United StatesDepartment of Medicine, University of California, San Francisco, San Francisco, United StatesMalaria Genetics and Resistance Unit, Institut Pasteur, INSERM U1201, CNRS ERL9195, Paris, FranceDivision of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, United StatesThe emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing of point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance.https://elifesciences.org/articles/66277Plasmodium falciparummalariaartemisinin resistanceCRISPR/Cas9ring-stage survivalfitness |
| spellingShingle | Barbara H Stokes Satish K Dhingra Kelly Rubiano Sachel Mok Judith Straimer Nina F Gnädig Ioanna Deni Kyra A Schindler Jade R Bath Kurt E Ward Josefine Striepen Tomas Yeo Leila S Ross Eric Legrand Frédéric Ariey Clark H Cunningham Issa M Souleymane Adama Gansané Romaric Nzoumbou-Boko Claudette Ndayikunda Abdunoor M Kabanywanyi Aline Uwimana Samuel J Smith Olimatou Kolley Mathieu Ndounga Marian Warsame Rithea Leang François Nosten Timothy JC Anderson Philip J Rosenthal Didier Ménard David A Fidock Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness eLife Plasmodium falciparum malaria artemisinin resistance CRISPR/Cas9 ring-stage survival fitness |
| title | Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness |
| title_full | Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness |
| title_fullStr | Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness |
| title_full_unstemmed | Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness |
| title_short | Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness |
| title_sort | plasmodium falciparum k13 mutations in africa and asia impact artemisinin resistance and parasite fitness |
| topic | Plasmodium falciparum malaria artemisinin resistance CRISPR/Cas9 ring-stage survival fitness |
| url | https://elifesciences.org/articles/66277 |
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